Deciphering the role of thromboxane A2 in mast cell-induced bronchoconstriction within human small airways

<bold>Introduction:</bold> Asthmatic bronchoconstriction induced by mast cells can be initiated through IgE crosslinking. The precise involvement of prostaglandins (PGs) in mediating these responses remains a topic of debate, prompting an investigation within isolated human small airways. <bold>Methods:</bold> Small airways (<2 mm inner diameter) from healthy human lung tissues (n=25) were isolated and mounted in tissue organ baths for measuring smooth muscle contractions induced by anti-IgE antibodies with or without pharmacologic inhibitors. EIA was used to assess PGs. Data presented as mean±SEM. <bold>Results:</bold> In controls, exposure to anti-IgE (5 µg/mL) caused a constriction (Emax:89±8%). Combined pretreatment with the antagonists for H₁ receptors (mepyramine;1 µM) and CysLT₁ receptors (montelukast;1 µM) reduced the anti-IgE induced contraction by 52±6%. The residual component of the contraction was abolished by addition of the cyclooxygenase (COX)-1 enzyme inhibitor FR 122,047 (1 µM), thromboxane(TX) A synthase inhibitor ozagrel (10 µM) or the TXA₂ TP receptor antagonist SQ-29,548 (1 µM). In addition, ozagrel not only completely prevented TXA₂ formation compared to control (8±3 vs. 102±35 pg/mg tissue) but also augmented the PGD₂ formation compared to control (362±61 vs. 262±52 pg/mg tissue). <bold>Discussion:</bold> Mast cell dependent contractions of human bronchi are mediated by histamine, cysteinyl-leukotrienes and COX-1 generated contractile prostanoids acting on the TP receptor. In addition, the inhibitor data support that TXA₂ is the primary contractile prostanoid in human small airways and that inhibition of its formation redirects formation towards PGD₂, suggesting a shunt of the endoperoxide PGH₂.